Hippocampal regulation and neuroprotection by NPC-derived VEGF

NPC 衍生的 VEGF 对海马的调节和神经保护

• 批准号: 8636917
• 负责人: Elizabeth Diana Kirby
• 金额: $ 5.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636917
• 关键词: Adult; Affect; Alzheimer' s Disease; Area; Astrocytes; Behavior; Blood Vessels; Blood capillaries; Brain; Cell Culture Techniques; Cell Proliferation; Cell Transplants; Cell physiology; Cells; Cognition; Cues; Data; Degenerative Disorder; Development; Disease model; Environment; Fibrinogen; Figs - dietary; Future; Generations; Genetic; Goals; Growth Factor; Growth Factor Overexpression; Healed; Hippocampus (Brain); In Vitro; Kainic Acid; Manuscripts; Measures; Modeling; Multiple Sclerosis; Mus; Nerve Block; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Neurosciences; Oligodendroglia; Parkinson Disease; Process; Property; Recombinant Vascular Endothelial Growth Factor; Recovery; Regulation; Research Design; Role; Secretory Cell; Signal Transduction; Source; Stem cell transplant; Stem cells; Techniques; Temporal Lobe Epilepsy; Testing; Therapeutic; Tissues; Transgenic Mice; Translational Research; Transplantation; Traumatic CNS injury; Undifferentiated; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Virus; angiogenesis; capillary; cell type; central nervous system injury; cytokine; excitotoxicity; experience; healing; human disease; in vivo; multipotent cell; nerve stem cell; nestin protein; neural model; neuroinflammation; neuron loss; neuroprotection; public health relevance; relating to nervous system; release factor; repaired; self-renewal; skills; small hairpin RNA; stem; stem cell therapy

DESCRIPTION (provided by applicant): Stem cell therapies hold great promise for treatment of human disease, particularly for currently incurable neurodegenerative diseases. However, to effectively harness the healing potential of stem cells, it is necessary to understand how these cells interact with and respond to their environment. In transplants, stem cells may function as replacement cells that respond to local cues to help mend damaged tissue. They may also function as a source of protective cues, secreting in their undifferentiated state growth factors that facilitate local repair processes. This proposal focuses on this second, less well understood role of stem cells as neuromodulatory secretory cells. The goal of this proposal is to investigate the regulatory and neuroprotective role of adult neural stem/progenitor cell (NPC)-derived secretions in the hippocampus. Given the prominent degradation of the hippocampus in several neurodegenerative disorders such as temporal lobe epilepsy and Alzheimer's disease, this brain area provides an attractive target for stem cell therapy. The Wyss-Coray lab has previously shown that isolated adult hippocampal NPCs secrete a variety of growth factors in large quantities, most notably the highly neuroprotective vascular endothelial growth factor (VEGF). My goal is to investigate the hypothesis that NPC- derived VEGF regulates hippocampal function and provides neuroprotection from degenerative disease. In Aim 1, I will determine how NPC-derived VEGF regulates the proliferation and differentiation of other NPCs in vitro and in vivo using genetic knockdown techniques specific to NPCs. In Aim 2, I will use the in vivo knockdown models from Aim 1 to determine how NPC- derived VEGF regulates the local vascular environment and hippocampal behavior in adult mice. Finally, in Aim 3, I will test the neuroprotective qualities of NPC-derived VEGF from endogenous NPCs (and from NPC transplants) in an excitotoxic model of neural insult. These studies will help provide critical understanding of how NPCs may function as future therapies in vivo. This project combines basic neuroscience with translational research, requiring that I become proficient in a broad skill set. I will gain experience in in vitro NPC culture, shRNA, lox- cre genetics, stereotaxic injectios into the hippocampus and neurodegenerative models of disease. Through this project, it is my goal to acquire expertise in translational research designed to pursue treatment for neurodegenerative disease.

描述（由申请人提供）：干细胞疗法对治疗人类疾病有很大的希望，特别是对于目前无法治愈的神经退行性疾病。但是，为了有效利用干细胞的愈合潜力，有必要了解这些细胞如何与其环境相互作用并响应。在移植物中，干细胞可能充当替代细胞，这些细胞对局部提示有助于修补损坏的组织。它们也可能是保护性线索的来源，以促进局部维修过程的未分化状态增长因素分泌。该提议重点是第二个，不太了解干细胞作为神经调节性分泌细胞的作用。该提案的目的是研究成年神经茎/祖细胞（NPC）衍生的海马分泌物的调节和神经保护作用。鉴于海马在几种神经退行性疾病（例如颞叶癫痫和阿尔茨海默氏病）中显着降解，该大脑区域为干细胞疗法提供了有吸引力的靶标。 Wyss-Coray Lab先前已经表明，分离的成年海马NPC分泌大量生长因子，最著名的是高度神经保护性血管内皮生长因子（VEGF）。我的目标是研究NPC衍生的VEGF调节海马功能并提供退化性疾病的神经保护的假设。在AIM 1中，我将使用NPC特定的遗传敲低技术来确定NPC衍生的VEGF如何在体外和体内调节其他NPC的增殖和分化。在AIM 2中，我将使用AIM 1的体内敲低模型来确定成年小鼠中NPC衍生的VEGF如何调节局部血管环境和海马行为。最后，在AIM 3中，我将在神经侮辱的兴奋性毒性模型中测试NPC衍生的NPC（以及NPC移植）的NPC衍生VEGF的神经保护品质。这些研究将有助于对NPC在体内的未来疗法中如何发挥批判性理解。该项目将基本的神经科学与转化研究结合在一起，要求我精通广泛的技能 放。我将获得体外NPC培养，ShRNA，Lox-Cre遗传学，立体定位注射的经验，并向海马和神经退行性模型。通过这个项目，我的目标是获得旨在追求神经退行性疾病治疗的翻译研究专业知识。